Genetic Variant UNC45B:p.Ile70Met (chr17-35150052-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001267052.2(UNC45B):c.210C>G(p.Ile70Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

UNC45B
NM_001267052.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.41

Variant links:

Genes affected

UNC45B (HGNC:14304): (unc-45 myosin chaperone B) This gene encodes a co-chaperone required for folding and accumulation of type II myosins. The protein consists of three tetratricopeptide repeat motifs at the N-terminus that form a complex with heat shock protein 90, a central region of unknown function that is conserved in all Unc-45 proteins, and a C-terminal Unc-45/Cro1/She4 domain. The protein is expressed at high levels in striated muscle, where its muscle myosin chaperone activity is dependent on heat shock protein 90 acting as a co-chaperone. A missense mutation in this gene has been associated with cataract development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

UNC45B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2 link	c.210C>G	p.Ile70Met	missense_variant	Exon 4 of 20	ENST00000394570.7	NP_001253981.1	Q8IWX7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UNC45B	ENST00000394570.7 link	c.210C>G	p.Ile70Met	missense_variant	Exon 4 of 20	1	NM_001267052.2	ENSP00000378071.2	Q8IWX7-3
UNC45B	ENST00000591048.2 link	c.210C>G	p.Ile70Met	missense_variant	Exon 3 of 17	1		ENSP00000468335.1	Q8IWX7-2
UNC45B	ENST00000268876.9 link	c.210C>G	p.Ile70Met	missense_variant	Exon 4 of 20	5		ENSP00000268876.4	Q8IWX7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

240842

Hom.:

AF XY:

0.00000769

AC XY:

AN XY:

130080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000347

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448892

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.11

CADD

Benign

2.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.81

D;D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Uncertain

2.9

M;M;M

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.98

N;N;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.011

D;D;.

Sift4G

Uncertain

0.036

D;D;D

Polyphen

0.92

P;P;P

Vest4

0.87

MutPred

0.66

Gain of disorder (P = 0.0795);Gain of disorder (P = 0.0795);Gain of disorder (P = 0.0795);

MVP

0.58

MPC

0.51

ClinPred

0.62

GERP RS

-5.2

Varity_R

0.15

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over